Deep learning assists detection of esophageal cancer and precursor lesions in a prospective, randomized controlled study.

Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.

Two Sesterterpene Synthases from Lentzea atacamensis Demonstrate the Role of Conformational Variability in Terpene Biosynthesis.

Mining of two multiproduct sesterterpene synthases from Lentzea atacamensis resulted in the identification of the synthases for lentzeadiene (LaLDS) and atacamatriene (LaATS). The main product of LaLDS (lentzeadiene) is a new compound, while one of the side products (lentzeatetraene) is the enantiomer of brassitetraene B and the other side product (sestermobaraene F) is known from a surprisingly distantly related sesterterpene synthase. LaATS produces six new compounds, one of which is the enantiomer of the known sesterterpene Bm1. Notably, for both enzymes the products cannot all be explained from one and the same starting conformation of geranylfarnesyl diphosphate, demonstrating the requirement of conformational flexibility of the substrate in the enzymes' active sites. For lentzeadiene an intriguing thermal [1,5]-sigmatropic rearrangement was discovered, reminiscent of the biosynthesis of vitamin D3. All enzyme reactions and the [1,5]-sigmatropic rearrangement were investigated through isotopic labeling experiments and DFT calculations. The results also emphasize the importance of conformational changes during terpene cyclizations.

Effect of Helicobacter pylori infection on body fat percentage in middle-aged and elderly populations.

Obesity, which is associated with excessive accumulation of body fat, is emerging as a new public health problem. Bioelectrical impedance analysis (BIA) is a non-invasive and straightforward method to analyze body composition, providing a more accurate estimate of obesity than the commonly used body mass index. The primary objective of this study was to examine the potential impact of Helicobacter pylori (H. pylori) infection on body fat percentage in a population using cross-sectional and cohort studies. METHODS: A population of people who underwent physical examinations at Taizhou Hospital between 2017 and 2022 was included. The participants underwent various tests, including urea breath test, hematological examination, and anthropometric measurement, in addition, their body fat percentage was determined through the use of BIA. Univariate and multifactorial regression analyses were conducted to identify factors associated with excess body fat. RESULTS: There was a difference in body fat percentage between H. pylori positive and negative populations. The population was divided into young and middle-aged and elderly according to age, and H. pylori infection was found to differ only in the middle-aged and elderly population. Multifactorial logistic regression showed that H. pylori infection remained associated with excess body fat in the middle-aged and elderly population. A subsequent cohort study confirmed the association of persistent H. pylori infection with excess body fat in the population. CONCLUSION: H. pylori was negatively associated with excess body fat in middle-aged and elderly populations, and long-term H. pylori infection has a negative effect on body fat in people.

Haptoglobin 2-2 Genotype is Related to the Severity of Liver Damage in Hepatitis B Patients with Liver Steatosis.

BACKGROUND: The Haptoglobin (Hp) genotypes have been linked to immune diseases and play a significant role in metabolic diseases. This study aimed to analyze the correlation between Hp gene polymorphism and the severity of hepatitis B accompanied by liver steatosis. METHODS: A total of 182 with Hepatitis B and concurrent hepatic steatosis were included in the study. Clinical biochemical indices for each participant were recorded. DNA was extracted from peripheral blood leukocytes for globin genotyping. Of these participants, 128 underwent biopsy from which histological data were collected. RESULTS: Subjects with hepatitis B and hepatic steatosis carrying the Hp 2-2 genotype exhibited elevated alanine transaminase (ALT), c-glutamyl transferase (GGT), and aspartate amino transferase (AST) levels. In contrast, high-density lipoprotein (HDL) levels and the copy number of Hepatitis B Virus (HBV)-DNA were significantly reduced in those with the Hp 2-2 genotype (p < 0.05). Furthermore, individuals processing the Hp 2-2 genotype demonstrated a heightened hepatitis score and advanced fibrosis stage (p < 0.05). Notably, the Hp 2-2 genotype was independently associated with increased inflammation (odds ratio (OR) = 7.059, p < 0.001) and progressive fibrosis (OR = 3.05, p < 0.022). CONCLUSIONS: The Hp 2-2 genotype is significantly associated with increased severity in cases of hepatitis B with coexisting hepatic steatosis.

Subrutilane-A Hexacyclic Sesterterpene from Streptomyces subrutilus.

Mining of a terpene synthase from Streptomyces subrutilus resulted in the identification of the hexacyclic sesterterpene subrutilane, besides eight pentacyclic side products. Subrutilane represents the first case of a saturated sesterterpene hydrocarbon. Its structure, including the absolute configuration, was unambiguously determined through X-ray crystallographic analysis and stereoselective deuteration. The cyclisation mechanism to subrutilane and its side products was investigated in all detail by isotopic labelling experiments and DFT calculations. The subrutilane synthase (SrS) also converted (2Z)-GFPP into one major product. Additional compounds were obtained from the substrate analogues (7R)-6,7-dihydro-GFPP and (2Z,7R)-6,7-dihydro-GFPP with blocked reactivity at the C6-C7 bond. Interestingly, the early steps of the cyclisation cascade with (2Z)-GFPP and the saturated substrate analogues were analogous to those of GFPP, but then deviations from the natural cyclisation mode occur.

Higher consumption of animal organ meat is associated with a lower prevalence of nonalcoholic steatohepatitis.

Background: Animal organ meat (offal) is a food with high nutrient density that is popular in different parts of the world, but its relationship with nonalcoholic steatohepatitis (NASH) is unclear. We aimed to examine whether daily animal organ meat consumption is associated with the presence of NASH in individuals with nonalcoholic fatty liver disease (NAFLD). Methods: A total of 136 Chinese adults with biopsy-proven NAFLD were included. Definite NASH was defined as NAFLD activity score ≥4 and at least one point for steatosis, ballooning, and lobular inflammation. Daily animal organ meat consumption was estimated using a self-administered validated food frequency questionnaire. Logistic regression analysis was performed to assess the association between animal organ meat intake and liver disease severity. Results: The 136 participants (80.9% men) of the study had a mean ± standard deviation (SD) age of 39.0±12.5 years and body mass index of 27.4±3.6 kg/m2. Prevalence of definite NASH was 65.4%. Daily median organ meat consumption was 1.30 g/1,000 kcal. Animal organ meat consumption was inversely associated with the presence of NASH even after adjustment of demographics, lifestyle variables, metabolic and dietary factors, as well as liver fibrosis stage; adjusted-odds ratios (95% confidence intervals) for NASH were 0.15 (0.03, 0.69) for the highest tertile and 0.18 (0.05, 0.70) for the medium tertile, compared to the lowest (reference) tertile of animal organ meat intake (P value for trend =0.024). Conclusions: Our results suggest for the first time that higher animal organ meat consumption is associated with a lower prevalence of NASH in Chinese individuals with biopsy-proven NAFLD.

Functional characterisation of twelve terpene synthases from actinobacteria.

Fifteen type I terpene synthase homologs from diverse actinobacteria that were selected based on a phylogenetic analysis of more than 4000 amino acid sequences were investigated for their products. For four enzymes with functions not previously reported from bacterial terpene synthases the products were isolated and their structures were elucidated by NMR spectroscopy, resulting in the discovery of the first terpene synthases for (+)-δ-cadinol and (+)-α-cadinene, besides the first two bacterial (-)-amorpha-4,11-diene synthases. For other terpene synthases with functions reported from bacteria before the products were identified by GC-MS. The characterised enzymes include a new epi-isozizaene synthase with monoterpene synthase side activity, a 7-epi-α-eudesmol synthase that also produces hedycaryol and germacrene A, and four more sesquiterpene synthases that produce mixtures of hedycaryol and germacrene A. Three phylogenetically related enzymes were in one case not expressed and in two cases inactive, suggesting pseudogenisation in the respective branch of the phylogenetic tree. Furthermore, a diterpene synthase for allokutznerene and a sesterterpene synthase for sesterviolene were identified.

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs.

Two aspects of the biosynthesis of the non-canonical terpene synthase for 2-methylisoborneol have been studied. Several 2-methylisoborneol synthases have a proline-rich N-terminal domain of unknown function. The results presented here demonstrate that this domain leads to a reduced enzyme activity, in addition to its ability to increase long-term solubility of the protein. Furthermore, the substrate scope of the 2-methylisoborneol synthase was investigated through enzyme incubations with several substrate analogs, giving access to two C12 monoterpenoids. Implications on the stereochemical course of the terpene cyclisation by 2-methylisoborneol synthase are discussed.

Persistent Helicobacter pylori infection leads to elevated fasting plasma glucose level: A retrospective cohort study based on a nondiabetes Chinese population.

BACKGROUND AND AIM: The relationship between Helicobacter pylori (H. pylori) and fast plasma glucose (FPG) on nondiabetes populations is still inconclusive. Nowadays, not only the high infection rate of H. pylori but also the high FPG level is threatening the Chinese people. METHODS: A retrospective cohort study has been established to analyze the relationship between H. pylori infection and FPG level, 18 164 individuals performed healthy examination in Taizhou Hospital Health Examination Center from 2017 to 2022 were included, and hematological indicators, body parameters, and H. pylori detection by 13 C-urea breath test were collected from patients. The follow-up intervals were greater than 12 months. RESULTS: H. pylori infection was regarded as an independent risk factor for elevated FPG after multivariate logistic regression. Additionally, the average interval time were 33.6 ± 13.3 months. Mean changed FPG values in the persistent infection group were higher than in the subgroup of persistent negative (P = 0.029) as well as eradication infection (P = 0.007). The aforementioned changes began to appear after 2 years of follow-up. Similarly, when compared with the subgroup of persistent infection, mean changed triglyceride/high density lipoprotein (TG/HDL) values were much lower in the subgroup of persistent negative (P = 0.008) and eradication infection (P = 0.018), but the differences appeared after 3 years of follow-up. CONCLUSIONS: H. pylori infection is an independent risk factor for elevated FPG in non-diabetes mellitus (DM) individuals. Persistent H. pylori infection causes an increase in FPG level and TG/HDL, which may be a risk factor for diabetes mellitus.

Ruptenes: A Family of Terpene Analogs Give Insight into Cyclisation Mechanisms by Cascade Disruption.

The terpenoid substrate analogs (7R)-6,7-dihydrogeranylgeranyl diphosphate (6,7-dihydro-GGPP) and (7R)-6,7-dihydrogeranylfarnesyl diphosphate (6,7-dihydro-GFPP) were synthesised from (S)-citronellol and enzymatically converted with nine diterpene and two sesterterpene synthases, respectively. In two cases the substrate analogs were converted into diterpenes in cyclisation reactions corresponding to those observed for the native substrate GGPP, while the cyclisation cascade was disrupted or redirected in the other nine cases, leading to products that were named ruptenes. Several of the isolated ruptenes represent deprotonation products of cationic intermediates that are analogs of the intermediates proposed along the cyclisation cascades for the native substrates GGPP or GFPP, thus giving insights into the complex reaction mechanisms of terpene synthase mediated biosynthesis.

Functional Characterisation of Highly Conserved and Structurally Prominent Residues of 2-Methylisoborneol Synthase.

2-Methylisoborneol is a widespread musty odourant that is produced by many bacteria including actinomycetes, cyanobacteria and myxobacteria. Two 2-methylisoborneol synthases (MIBS) that are phylogenetically distant to the known enzyme from Streptomyces coelicolor were found to be highly active for 2-methylisoborneol biosynthesis. Based on the enzyme structure and on an amino acid sequence alignment, the MIBS from S. coelicolor was extensively studied through site-directed mutagenesis.

ARL9 is upregulated and serves as a biomarker for a poor prognosis in colon adenocarcinoma.

BACKGROUND: ARL9 is a newly identified member of the ARF family, and the clinical significance of ARL9 in colon adenocarcinoma is unknown. In this study, we aimed to explore the expression of ARL9 mRNA in colon adenocarcinoma, and its effect on the prognosis of patients with colon adenocarcinoma. METHODS: We investigated the differential expression of ARL9 between colon adenocarcinoma tissue and adjacent tissues through a bioinformatics analysis using The Cancer Genome Atlas (TCGA) database. The correlation between clinical characteristics and the mRNA expression level of ARL9 were analyzed. A survival analysis and a Cox regression analysis were used to determine the prognostic significance of ARL9. Finally, we conducted a gene set enrichment analysis (GSEA) to explore the ARL9 signaling pathways involved in the development of colon adenocarcinoma. The effect of the expression of ARL9 on the proliferation and migration of colon adenocarcinoma was analyzed by the CCK8 method and a cell scratch test, respectively. RESULTS: The mRNA expression of ARL9 in colon adenocarcinoma tissues was higher in comparison to the level in normal adjacent tissues (P < 0.05). The mRNA expression of ARL9 was not related to sex, tumor stage, T stage, N stage, M stage, but to age. The 5-year survival rate of colon adenocarcinoma patients with high ARL9 mRNA expression levels was significantly lower than that of patients with low ARL9 mRNA expression levels (P < 0.05). Age and the high mRNA expression of ARL9 were independent risk factors for a poor prognosis in patients with colon adenocarcinoma. The GSEA suggested that ARL9 may be able to upregulate cell adhesion, extracellular matrix receptor interactions, tumor-associated pathways, and downregulate the citrate cycle and tricarboxylic acid cycle pathway, which are involved in the development of colon adenocarcinoma. After knocking down ARL9, the proliferation and migration abilities of colon adenocarcinoma cells were decreased (P < 0.01). CONCLUSION: The mRNA expression of ARL9 is upregulated in colon adenocarcinoma, and higher mRNA expression levels are associated with a poor prognosis. Knocking down ARL9 can reduce the proliferation and migration of colon adenocarcinoma cells. ARL9 mRNA can be used as a prognostic biomarker in patients with colon adenocarcinoma.

Association of KMT2C/D loss-of-function variants with response to immune checkpoint blockades in colorectal cancer.

Immune checkpoint inhibitors (ICIs) have become important treatment strategies, yet responses vary among patients and predictive biomarkers are urgently needed. Mutations in KMT2C and KMT2D lead to increased levels of genomic instability. Therefore, we aimed to examine whether KMT2C/D mutations might be a predictor of immunotherapeutic efficacy. Here, we investigated the associations of KMT2C/D loss-of-function (LOF) variants with tumor mutation burden (TMB), MSI-H, PD-L1 expression, the levels of tumor-infiltrating leukocytes (TILs), and clinical response to ICIs. It was found that KMT2C/D LOF variants were associated with higher TMB. Compared with the non-LOF group, the proportion of patients with MSI-H tumors was larger in the LOF group. PD-L1 expression was higher in the LOF group only for colorectal cancer in both the Chinese and The Cancer Genome Atlas cohorts. Importantly, KMT2C/D LOF variants were associated with decreased regulatory T cells and increased levels of CD8+ T cells, activated NK cells, M1 macrophages, and M2 macrophages in colorectal cancer. However, there was no significant association between KMT2C/D LOF and TILs levels in other cancer types. Consistently, the results showed that KMT2C/D LOF variants were associated with prolonged overall survival only in colorectal cancer (p = 0.0485). We also presented that patients with KMT2C/D LOF mutations exhibited a better clinical response to anti-PD-1 therapy in a Chinese colorectal cancer cohort (p = 0.002). Taken together, these results suggested that KMT2C/D LOF variants could be a useful predictor for ICIs efficacy in colorectal cancer. In addition, the predictive value of KMT2C/D LOF variants was consistent with their association with TILs levels.

Mechanistic Characterisation and Engineering of Sesterviolene Synthase from Streptomyces violens.

The sesterviolene synthase from Streptomyces violens was identified and represents the second known sesterterpene synthase from bacteria. Isotopic labelling experiments in conjunction with DFT calculations were performed that provided detailed insight into its complex cyclisation mechanism. Enzyme engineering through site-directed mutagenesis gave access to a high-yielding enzyme variant that provided six additional minor products and the main product in sufficient quantities to study its chemistry.

Risk Factors for Radiological Progression Within Admissive One Week in the Hospitalized COVID-19 Omicron Variant-Infected Patients.

Purpose: Recently, the SARS-CoV-2 Omicron variant was identified as responsible for a novel wave of COVID-19 worldwide. We perform a retrospective study to identify potential risk factors contributing to radiological progression in the COVID-19 patients due to the Omicron variant infection. These findings would provide guiding information for making clinical decisions that could improve the Omicron infection prognosis and reduce disease-related death. Methods: This is a retrospective cohort study from a single center in China. According to the radiological change within admissive one week, enrolled cases were divided into two groups: the progressive (1w-PD) and the stable or improved disease (1w-non-PD). Separate analyses were performed on patients stratified into subgroups using the Mann-Whitney U-test, the Fisher exact test, or the Chi-squared test and a multivariable logistic regression analysis. Results: Both the 1w-non-PD and 1w-PD cohorts displayed comparable asymptomatic infection, have similar underlying disease, impairment in respiratory function, coagulation dysfunction, tissue injury, SARS-CoV-2 viral load, and disease severity. However, the 1w-PD cohort was more inclined to cluster in populations presented with age between 41 and 65, higher CURB-65 scores, undetectable SARS-CoV-2 IgG, and lung affection. Based on the multiple logistic regression analysis, complicated bilateral and ground-glass opacities (GGOs) like pneumonia at admission were independent risk factors to radiological progression within admissive one week. Conclusion: This study provided preliminary data regarding disease progression in Omicron-infected patients that indicated the development of pneumonia in the context of Omicron infection was worthy of potential risk factors.

Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital.

Considerable attention has been focused on the clinical features of coronavirus disease 2019 (COVID-19), but it is also important for clinicians to differentiate it from influenza virus infections. In the present study, the rate of coexisting disease was lower in the severe COVID-19 group than in the influenza A group (p = 0.003). Radiologically, severe COVID-19 patients had fewer instances of pleural effusion (p < 0.001). Clinically, severe COVID-19 patients had relatively better disease severity scores, less secondary bacterial infections, shorter times to beginning absorption on computed tomography, but longer durations of viral shedding from the time of admission (p < 0.05). Although the more severe influenza A patients required noninvasive respiratory support, these two groups ultimately yielded comparable mortalities. Based on the multiple logistic regression analysis, severe COVID-19 infection was associated with a lower risk of severe acute respiratory distress syndrome [odds ratio (OR) 1.016, 95% [confidence interval (CI)] 1.001-1.032, p = 0.041] and a better pneumonia severity index (OR 0.945, 95% [CI] 0.905-0.986, p = 0.009); however, these patients exhibited longer durations of viral shedding (OR 1.192, 95% [CI] 1.047-1.357, p = 0.008) than patients with severe influenza A infection. In conclusion, the conditions of severe influenza A patients appeared to be more critical than that of severe COVID-19 patients. However, relatively lower mortalities of these two severe cases are expected in the context of sufficient medical supplies.

The stereochemical course of 2-methylisoborneol biosynthesis.

Both enantiomers of 2-methyllinalyl diphosphate (2-Me-LPP) were synthesized enantioselectively using Sharpless epoxidation as a key step and purification of enantiomerically enriched intermediates through HPLC separation on a chiral stationary phase. Their enzymatic conversion with 2-methylisoborneol synthase (2MIBS) demonstrates that (R)-2-Me-LPP is the on-pathway intermediate, while a minor formation of 2-methylisoborneol from (S)-2-Me-LPP may be explained by isomerization to 2-Me-GPP and then to (R)-2-Me-LPP.

Comparison of initial clinic characteristics of hospitalized patients in Suzhou City during the COVID-19 Omicron wave with ancestral variant wave.

BACKGROUND: Recently, the SARS-CoV-2 variant of concern, Omicron (B.1.1.529), was identified as responsible for a novel wave of COVID-19 worldwide. Here, we compared initial clinical features of hospitalized COVID-19 patients during recent wave (Omicron Variant) with those in ancestral variant wave (2020). METHODS: This is a cohort study of electronic health record (EHR) data from a signal center in the China. The clinical data of 116 cases of Omicron hospitalized in 2022 and 87 cases hospitalized in 2020 were collected. The comparisons were performed with the Mann-Whitney U test, Fisher exact test or the chi-square test, and multivariable logistic regression analysis. RESULTS: Clinically, compared with 2020-cohort, Omicron-cohort was more inclined to cluster in younger population and had more nonsymptomatic (25.0%) and nonsevere cases, as well as suffered from comparable extrapulmonary complication. Radiologically, although the major computed tomography (CT) findings of both cohorts were ground-glass opacities (GGOs), crazy-paving pattern was relatively less seen in the Omicron-cohort. Based on multiple logistic regression analysis, Omicron-cohort was associated with a lower risk of complaining with fever, the presence of lung opacity, and increased Sequential Organ Failure Assessment (SOFA) score. CONCLUSION: This study provided the data of different patterns of clinic characteristics and reduced severity from infections that occurred in Omicron variant as compared with the outbreak of the epidemic in 2020 wave (ancestral variant).

Distribution and clinical significance of circulating CD8+CD28- regulatory T cells in the peripheral blood of patients with pulmonary tuberculosis.

BACKGROUND: Regulatory T cells (Treg cells) in the peripheral blood of patients with pulmonary tuberculosis (PTB) may be closely related to the progression of PTB. In this study, the distribution characteristics and clinical importance of CD8+CD28- Treg cells in patients with tuberculosis were systematically analyzed, and the role and importance of CD8+CD28- Treg cells in influencing the immune response and progression of tuberculosis were discussed, which will provide immunological indices and reference values for the clinical diagnosis of tuberculosis. METHODS: Flow cytometry, sputum smears and computed tomography imaging were used to analyze the distribution characteristics of CD8+CD28- Treg cells in the peripheral blood of patients with PTB and the correlation between CD8+CD28-Treg cells and clinical and immune indices. RESULTS: The percentages of CD4+CD25high and CD8+CD28- Treg cells in the peripheral blood of patients with PTB were significantly higher than those in the healthy control (HC) group. Further analysis showed that the percentage of CD4+CD25highTreg cells in the Stage II group was significantly higher than that in the HC group. The percentages of CD4+CD25high and CD8+CD28- Treg cells increased significantly in patients in the Stage II group. The proportion of CD8+CD28- Treg cells was directly proportional to the degree of positivity in sputum smears, while CD4+CD25highTreg cells did not exhibit this trend. The correlations between the percentage of CD4+CD25high and CD8+CD28- Treg cells and the percentage of lymphocyte subsets were examined. The percentage of CD8+CD28- Treg cells was negatively correlated with the percentage of CD4+T cells and positively correlated with the CD8+T cell percentage in the HC and PTB groups. The percentage of CD4 + CD25highTreg cells was positively correlated with the percentage of CD4+T cells only in the PTB group. CONCLUSIONS: This study was the first to show that the proportion of CD8+CD28- Treg cells in the peripheral blood of patients with PTB was significantly increased, and the increase in CD8+CD28- Treg cells was related to the progression of PTB, which may affect the proportion of immune cell subsets by inhibiting the immune response, resulting in the progression of PTB.